Furmonertinib for EGFR-mutant advanced non-small cell lung cancer: a glittering diamond in the rough of EGFR-TKI

The third-generation EGFR-TKIs, such as osimertinib, aumolertinib, and furmonertinib, have been recommended as the preferred treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). Among them, furmonertinib shows several advantages in terms of clinical efficacy. Firstly, compared to osimertinib and aumolertinib, furmonertinib was the first EGFR-TKI with median progression-free survival (mPFS) of over 20.0 m (20.8 m) for advanced NSCLC with classical EGFR-mutations. Furthermore, furmonertinib achieved a mPFS of 18.1 m in advanced NSCLC with unfavorable prognostic factors, such as the 21 L858R mutation and central nervous system (CNS) metastasis, which is unrivalled by osimertinib. Secondly, furmonertinib is the only FDA-approved EGFR-TKI for breakthrough therapy in newly-diagnosed advanced NSCLC with EGFR ex20ins mutation. Thirdly, the relatively longer mPFS of 20.8 m was observed in furmonertinib compared to osimertinib and aumolertinib (15.2 m and 15.3 m) in EGFR-mutant advanced NSCLC with CNS metastases. More importantly, the efficacy of furmonertinib increases within the dose range of 80–240 mg per day. Finally, furmonertinib can be an optional treatment for advanced NSCLC patients who develop resistance to osimertinib or aumolertinib. In conclusion, furmonertinib may be a glittering star in the field of EGFR-TKI, which requires further exploration and expansion.


Introduction
The discovery of the first driver gene, the epidermal growth factor receptor (EGFR), has ushered in the era of personalized and precise medical treatment for non-small cell lung cancer (NSCLC).The prevalence of EGFR mutation is 10%-20% in Caucasian populations, but can be as high as 50% in Asian patients (Wu and Zhou, 2023).EGFR tyrosine kinase inhibitor (EGFR-TKI) agents have revolutionized the therapeutic strategy for NSCLC with EGFR mutations.Since the introduction of the first EGFR-TKI (gefitinib), there has been a continuous emergence of newer generations of EGFR-TKI over the past 2 decades, including the 1st-generation (gefitinib, erlotinib, icotinib), the 2nd-generation (afatinib, dacomitinib), and the 3rd-generation (osimertinib, aumolertinib, furmonertinib).According to the 2023 Chinese Society of Clinical

Furmonertinib for advanced NSCLC harboring EGFR exon 20 insertions
As the third most common type of EGFR mutation, exon 20 insertions (EGFR ex20ins) represent up to 12% of all EGFRmutant NSCLC with 5-year OS of 8%.Patients with NSCLC harboring ex20ins exhibit a mPFS of 3.4-6.9months and an  1).Thus, in October 2023, the U.S. Food and Drug Administration granted breakthrough therapy status to furmonertinib for the treatment of newly-diagnosed advanced NSCLC with EGFR ex20ins mutation.
A preclinical data demonstrated furmonertinib targeting G719S (Ba/F3 cellular IC50 = 12.4 nM), S7681 (Ba/F3 cellular IC50 = 21.6 nM) and L861Q (Ba/F3 cellular IC50 = 3.8 nM) (Musib et al., 2022).Zhao Y et al. reported a female advanced NSCLC with original EGFR L861Q mutation and secondary MET amplification, who progressed after osimertinib plus chemotherapy, and afatinib treatment.The patient received combined treatment of furmonertinib with crizotinib.Encouragingly, she achieved partial remission with a PFS of 6 months, indicating the potential candidate to overcome the resistance of osimertinib and afatinib (Zhao et al., 2023).The results strongly suggested that furmonertinib could be regarded as a potent agent against the uncommon EGFR mutations.A clinical study (NCT05548348) is in recruiting stage in which furmonertinib (160 mg/day) is employed to treat advanced NSCLC patients harboring uncommon EGFR mutations (Table 2).The study is still ongoing, and the results are worth expecting.

Furmonertinib for advanced NSCLC with central nervous system metastases
Central nervous system (CNS) is a common site of metastases in patients with EGFR-mutated NSCLC, and is associated with a poor prognosis.For all patients with CNS metastases, osimertinib showed a better mPFS compared to gefitinib/erlotinib (15.2 vs. 9.6 months, p < 0.001; HR = 0.47, 0.30-0.74) in FLAURA study (Soria et al., 2018).Similarly, the mPFS for the aumolertinib and gefitinib group was 15.3 months and 8.2 months, respectively (HR = 0.38, 0.24-0.60)(Lu et al., 2022).The FURLONG study showed that furmonertinib prolonged the mPFS to 20.8 months compared to gefitinib (9.8 months) for patients with CNS metastases (HR = 0.40, 0.23-0.71)(Shi et al., 2022b).Comparatively, furmonertinib exhibited superior efficacy in terms of PFS compared to osimertinib and aumolertinib.Furthermore, a post hoc analysis was conducted in 52 NSCLC patients with EGFR-mutation and CNS metastases who received furmonertinib treatment ranging from 40 mg/d to 240 mg/d.The CNS-ORR were 65% for 80 mg/d group and 85% for 160 mg/d group.The median CNS-PFS for 40 mg/day, 80 mg/d, 160 mg/day, and 240 mg/day was 2.8 months, 11.6 months, 19.3 months and not reached (NR) respectively, suggesting a dose-dependent effect of furmonertinib (Hu et al., 2023) (Table 1).These findings supported furmonertinib as a preferred treatment option for EGFR-mutant NSCLC with concurrent CNS metastases.

Furmonertinib for advanced NSCLC after osimertinib/aumolertinib resistance
Osimertinib commonly exhibits an initial positive response in advanced NSCLC with classical EGFR mutation.However, acquired resistance to osimertinib is inevitable.Recently, researchers have investigated the therapeutic strategy of among the third-generation EGFR-TKI.In arealworld study, 39 patients with EGFR-mutated NSCLC received the innovative re-challenge of furmonertinib (160 mg/d) after resistance to osimertinib or aumolertinib (Table 1) (Qi et al., 2023).The DCR was 79.5% and the mPFS was 4.7 months with the maximum PFS of nearly 13.8 months, which outperformed previously reported strategies.Encouragingly, the patients in the intracranial progression (IP group, N = 22) had markedly higher mPFS and mOS than those in the extracranial progression (EP group, N = 17) (5.5 vs. 3.2 months, p = 0.0018; 9.8 vs. 6.7 months, p = 0.021).Thus, furmonertinib displayed favorable efficacy in patients with IP, suggesting that furmonertinib possessed greater penetration of blood-brain barrier compared to osimertinib or aumolertinib.
The underlying mechanism may be associated with the unique pharmacological and physiological features of furmonertinib.As a novel third-generation EGFR-TKI, furmonertinib introduces the innovative trifluoroethoxypyridine structure.Firstly, in vivo studies have shown that furmonertinib irreversibly inhibits EGFR-sensitive and resistant mutations, such as G719X, 19 del, 21 L858R, L861Q, and T790M (Musib et al., 2022).In terms of pharmacology, the active metabolite AST5902 has similar   Musib et al., 2022), indicating "dual antitumor activity".Secondly, the introduction of the trifluoroethoxypyridine structure significantly improved the lipid solubility of the furmonertinib prototype and its metabolites.An in vitro study found that the intracranial uptake of furmonertinib and AST5902 was four times higher than that of osimertinib (Shi et al., 2020), suggesting "dual brain entry".Thirdly, unlike osimertinib, furmonertinib and AST5902 are not substrates of the efflux transporter (i.e., P-gp) and thus easily cross the bloodbrain barrier, supporting high selectivity for intracranial metastases (Shi et al., 2020).Finally, compared to EGFR mutants, furmonertinib and AST5902 have a lower inhibitory capability on wild-type EGFR and other related receptors (Meng et al., 2022;Musib et al., 2022), which partly explain the good safety profile of high-dose furmonertinib for human.These findings suggested that furmonertinib (160 mg/d) may be a novel rescue strategy for those patients after osimertinib or aumolertinib failure.

Safety profile of furmonertinib
Besides clinical efficacy, the safety profile is another important issue to consider in clinical settings.As shown in (Table 2), the diarrhea incidence of furmonertinib was marginally higher than osimertinib and aumolertinib (27% vs. 24% vs. 16.4%).The incidences of Q-T intervals prolongation were nearly similar among the three drugs.More importantly, the lowest frequencies of other treatment-related adverse effects (TRAEs) were observed in the group of furmonertinib, including skin rash, leucopenia, thrombocytopenia, anemia, interstitial lung disease (ILD), and creatine phosphokinase (CPK) elevation.As can be seen from the (Table 2), furmonertinib exhibited better safety profile when compared with osimertinib and aumolertinib.
The FAVOUR study (NCT04858958) aimed to explore the realworld efficacy and safety of furmonertinib in advanced NSCLC patients harboring EGFR ex20ins.In the study, the most common TRAEs were diarrhea (26.4%) and rash (26.4%).Even in the group receiving 240 mg/d of furmonertinib, no TRAEs of grade ≥3 were found.Furthermore, there was no statistically significant difference observed in the incidence of TRAEs within the dosage range of 80-240 mg of furmonertinib (p = 0.271) (Sa et al., 2023).Thus, furmonertinib had a good safety profile without dosedependent toxicity.
first-line treatment of furmonertinib is being launched in advanced NSCLC patients with uncommon EGFRmutations (NCT05548348) (Table 3).

Concluding remarks of furmonertinib
Furmonertinib, as a novel 3rd-generation EGFR-TKI, demonstrates excellent clinical efficacy, a good safety profile, and a wide therapeutic window (80mg-240 mg) in advanced NSCLC with EGFR classical and CNS metastases.Furthermore, furmonertinib shows superior efficacy in patients with exon 20 insertions mutations, which is unrivalled by osimertinib and aumolertinib.In particular, furmonertinib possesses better effect on NSCLC patients after osimertinib or aumolertinib resistance (Figure 1).There are grounds to believe that furmonertinib will be of promising prospect to treat the vast majority activating EGFRmutant NSCLC.

TABLE 1
Prospective and retrospective clinical study of third-generation EGFR-TKI treatment for advanced EGFR-mutant NSCLC.

TABLE 1 (
(Sa et al., 2023)ctive and retrospective clinical study of third-generation EGFR-TKI treatment for advanced EGFR-mutant NSCLC.Moreover, the ORR increased with the dose intensity, with rates of 25.0% for 80 mg/d, 39.5% for 160 mg/d, and 42.9% for 240 mg/d (p = 0.816).Importantly, patients with CNS metastases possessed similar ORR to those without CNS metastases (33.3% vs. 40.6%,p=0.773).The efficacy of furmonertinib was independent of the location of the EGFR ex20ins mutation(Sa et al., 2023)(Table

TABLE 3
Ongoing clinical study of furmonertinib treatment for EGFR-mutant NSCLC.